The competing renewal of this program project builds on important findings from the initial funding period. These findings have served to advance our understanding of the mechanisms of islet beta cell destruction and recurrence of autoimmune diabetes in the setting of islet or pancreas transplantation. The central theme of the present program project is the continuation of studies focused on the elucidation of mechanisms governing progression to autoimmune disease. These investigations will pertain to the underlying reason(s) for the formation of a diabetogenic T cell repertoire and the in situ events mediation beta cell apoptosis in an inflammatory setting. Critical events of cross-talk exist between the investigators; the way in which cytokine mediated death signals are translated to the activation of islet intrinsic death pathways will be the center piece of cross-talk between Drs. Birnbaum and Wolf. Dr. Birnbaum will extend his findings at the level of intrinsic biochemical beta cell death pathways to the prevention of islet graft rejection in transplantation models developed by Dr. James Markmann.. The relevance of the various death pathways to diabetogenesis in NOD mice will be studied through a collaborative series of experiments between Drs. Naji and Birnbaum. Insight into such basic processes will be extended by Dr. Markmann to the design of clinical intervention strategies aimed at the prevention of recurrent anti-beta cell autoimmunity in a transplant setting. Collectively, we have assembled a core of scientists from the departments of medicine, Pathology and Laboratory Medicine, Immunology and Surgery to focus their investigative efforts on addressing a central question: What are the mechanisms governing progression and recurrence of autoimmune diabetes in genetically susceptible individuals?